UNIQUE PATIENT POPULATIONS
Expansions and notes for abbreviations used in this section can be found in Methods Table 3.
1. Patients with HIV/HCV Coinfection
The summary of recommendations for HIV-coinfected patients is in the Unique Patient Populations: HIV/HCV Coinfection Box.
HIV/HCV coinfection results in increased liver-related morbidity and mortality, non-hepatic organ dysfunction, and overall mortality. Even in the potent antiretroviral era, HIV infection remains independently associated with advanced liver fibrosis and cirrhosis in patients with HCV coinfection. (Thein, 2008); (de Ledinghen, 2008); (Fierer, 2013) Similar to HCV-monoinfected patients, HIV/HCV-coinfected patients cured with PEG/RBV have lower rates of hepatic decompensation, hepatocellular carcinoma, and liver related mortality. (Berenguer, 2009); (Limketkai, 2012); (Mira, 2013) Uptake of HCV therapy is limited in the HIV/HCV-coinfected population due to historically lower response rates, patient comorbidities, patient and practitioner perception, and the adverse events associated with IFN-based therapy. (Mehta, 2006); (Thomas, 2008) Due to the special population designation, the first 2 approved DAAs, telaprevir and boceprevir, remain off label for use in HIV/HCV-coinfected patients, further limiting access to treatment in this population. With the availability of the DAAs sofosbuvir and simeprevir, a milestone has been reached in HIV/HCV coinfected patients. Treatment of HIV/HCV-coinfected patients requires awareness and attention to the complex drug interactions that can occur between DAA and HIV antiretroviral medications.
Pharmacokinetics and Drug Interactions
Sofosbuvir is not metabolized by the hepatic P450 enzyme complex and is a substrate (but not an inhibitor) of drug transporters, p-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). It is not a substrate of OATP. Drug interaction studies with antiretroviral drugs (ie, efavirenz, tenofovir, emtricitabine, rilpivirine, darunavir/ritonavir, and raltegravir) in non-infected persons identified no clinically significant interactions (Kirby, 2013) making sofosbuvir an ideal therapy for patients with HIV/HCV coinfection. Sofosbuvir is not recommended for use with tipranavir because of the potential of this antiretroviral drug to induce P-gp (see package insert).
Simeprevir is metabolized primarily by cytochrome P450 3A4 (CYP3A4) and therefore is susceptible to drug interactions with inhibitors and inducers of the enzyme. Simeprevir is also an inhibitor of the OATP and P-gp transporters leading to additional drug interaction concerns. Drug interaction studies with antiretroviral drugs in non-infected volunteers suggested no substantial interactions with tenofovir, rilpivirine, or raltegravir; however, simeprevir concentrations were substantially decreased when dosed with efavirenz and substantially increased when dosed with darunavir/ritonavir, resulting in their exclusion from the Phase III C212 clinical trial investigating simeprevir in combination with PEG/RBV in patients with HIV/HCV coinfection. (Ouwerkerk-Mahadevan, 2012)
Ribavirin has the potential for dangerous drug interactions with didanosine resulting in mitochondrial toxicity with hepatomegaly/steatosis, pancreatitis, and lactic acidosis; thus the concomitant administration of these 2 drugs is contraindicated. (Fleischer, 2004) The combined use of RBV and zidovudine has been reported to increase the rates of anemia and the need for RBV dose reduction, and thus zidovudine is not recommended for use with RBV. (Alvarez, 2006)
Sofosbuvir (400 mg once daily) as part of a triple-therapy regimen with PEG (180 μg weekly) and weight-based RBV (1000 mg to 1200 mg daily given in divided doses) is safe and efficacious in patients with HCV monoinfection, with an overall SVR12 of 89% in HCV genotype 1 patients. The P7977-1910 study was a single-center, single-arm trial (N=23) investigating this same 12-week triple therapy regimen in HIV-infected patients coinfected with HCV genotypes 1, 2 3, or 4. (Rodriguez-Torres, 2013) Allowable antiretrovirals included either efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir, or rilpivirine in combination with tenofovir/emtricitabine. Of patients with HCV genotype 1 (N=19), 89% achieved SVR12; 2 patients discontinued the study early due to adverse events (ie, anemia and altered mood). This regimen is therefore recommended for persons with HIV/HCV genotype 1 coinfection who are eligible to receive IFN and are either treatment-naive or have had prior PEG/RBV relapse.
The Phase III PHOTON-1 study enrolled 182 treatment-naive patients with HIV/HCV coinfection (n=114 with genotype 1; n=26 with genotype 2; n=42 with genotype 3) in a single-arm clinical trial investigating sofosbuvir (400 mg once daily) plus weight-based RBV (1000 mg to 1200 mg daily given in divided doses) for 24 (genotype 1) or 12 (genotypes 2 and 3) weeks. (Sulkowski, 2013c) The population had well-controlled HIV with mean CD4 counts of 559 to 636 cells/μL. The same ARVs were allowed as those in the P7977-1910 study. Of participants, 90% completed treatment and 3% discontinued treatment due to adverse events. SVR12 was achieved in 76%, 88%, and 67% of participants with HCV genotypes 1, 2, and 3, respectively. For the combination of sofosbuvir plus RBV, genotype 1b subtype was a predictor of poorer response. Cirrhosis and African American race also exhibited trends toward lower SVR12. Based on the potential for lower response in HIV/HCV-coinfected patients with cirrhosis, the use of sofosbuvir plus PEG/RBV should be considered over sofosbuvir plus RBV. This regimen is otherwise recommended for HIV/HCV genotype 1-coinfected patients who are treatment naive or have relapsed after receipt of PEG/RBV and are ineligible for IFN.
The combination of simeprevir plus sofosbuvir with or without RBV has been studied in the phase II COSMOS trial in patients with HCV monoinfection. (Jacobson, 2013b) This study is the basis for the recommendation supporting the use of this all-oral combination as an alternative regimen for patients with HCV monoinfection who cannot tolerate the recommended regimens. Although sofosbuvir plus simeprevir has been used anecdotally in patients with HIV/HCV coinfection, this drug combination has never been studied in this population. Despite the absence of data, this regimen may be considered for the treatment of HCV genotype 1 infection in patients with HIV infection who are not eligible for IFN and who are receiving antiretroviral therapy that may be coadministered with simeprevir (ie, raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, and abacavir).
Similarly, no data exist for the combination of sofosbuvir plus simeprevir for the (re)treatment of HCV infection in HIV-infected patients. However, preliminary results obtained in HCV-monoinfected patients, including those with prior treatment failure and advanced fibrosis, support the expectation that this regimen will be highly effective in coinfected patients receiving compatible antiretroviral therapy as described above (see Retreatment of HCV Monoinfected Patients). (Jacobson, 2013b) Given the lack of clinical data in this population, it may be prudent to reserve this regimen for the treatment of persons with advanced fibrosis in whom a delay of therapy may lead to adverse clinical outcomes.
No data with sofosbuvir currently exist to guide retreatment recommendations for coinfected patients with HCV genotype 2 or 3 HCV infection. The ongoing PHOTON-1 study enrolled 41 treatment-experienced patients coinfected with HCV genotype 2 or 3, receiving sofosbuvir (400 mg once daily) plus weight-based RBV (1000 mg to 1200 mg daily given in divided doses) for 24 weeks. (Sulkowski, 2013b) Results are expected in early 2014. In the absence of data, current recommendations for the retreatment of HIV patients coinfected with HCV genotype 2 or 3 are the same as those for HCV-monoinfected patients. Data also are lacking regarding use of sofosbuvir among patients coinfected with HCV genotype 4, 5, or 6 and HIV. Similarly, with no current data on the use of sofosbuvir in patients with genotype 4, 5, or 6 HCV and HIV coinfection, but given evidence of safety and efficacy of sofosbuvir-based regimens in this population, the recommended regimens for treatment in treatment-naive and treatment-experienced patients with HIV/HCV coinfection are the same as those for HCV-monoinfected patients.
The TMC435-C212 is a Phase III, open-label, single-arm study investigating simeprevir plus PEG/RBV (fixed-dose ribavirin) in treatment-naive and treatment-experienced patients coinfected with HCV genotype-1 and HIV. (Dieterich, 2013) The study used an RGT design for treatment-naive and prior PEG/RBV relapsers; prior partial and null responders and all patients with cirrhosis (regardless of treatment history) received 48 weeks of therapy (SMV x 12 weeks plus PEG/RBV x 48 weeks). The primary analysis reported an overall SVR12 of 74% (treatment naive: 79%; prior relapsers, 87%: prior partial responders: 70%; prior null responders: 57%). Most (89%) eligible patients met criteria for RGT and were able to shorten therapy to 24 weeks, after which time 78% achieved SVR12. Lower SVR12 was reported in several clinically relevant subgroups: genotype 1a (71% vs 89% in genotype 1b); genotype 1a with the Q80K mutation at baseline (67%); advanced fibrosis or cirrhosis (64%); IL28B unfavorable genetic polymorphisms (68% and 61% for the CT and TT variants vs 96% for the favorable CC variant); high baseline HCV RNA (70% for >800,000 IU/mL or 93% for <800,000 IU/mL); and patients not receiving antiretroviral therapy (62% vs 75% in subjects on antiretroviral drugs). As with patients with HCV monoinfection, baseline resistance testing for the Q80K polymorphism should be performed in all patients harboring the genotype 1a subtype and a different regimen considered if the polymorphism is present. Virologic failures occurred; most failures (79%) were associated with the emergence of resistant-associated mutations.
The adverse event profile was similar to that of patients with HCV monoinfection, with a higher frequency of pruritus, rash, photosensitivity, and increased bilirubin than is observed in patients receiving PEG/RBV alone. Due to the complexity of antiretroviral drug-associated drug interactions with simeprevir, the longer course of PEG/RBV, the adverse effect profile, and the risk of resistance emergence with treatment failure, simeprevir plus PEG/RBV is considered an alternative regimen for treatment-naive and prior PEG/RBV relapse patients with HIV coinfection with genotype HCV who cannot tolerate the recommended regimens. This regimen is not recommended in prior nonresponders or patients with cirrhosis because of observed lower response rates seen and the poor tolerability of 48 weeks of PEG/RBV. Due to diminished activity in vitro (for genotype 2 and 3) and insufficient data (for genotype 4) this regimen cannot be recommended for these genotypes.
Sofosbuvir plus PEG/RBV has not been studied in patients with HIV/HCV genotype 1 coinfection in whom previous IFN-based HCV therapy has failed. However, in a study of a limited number of patients (n=19), the efficacy of this regimen in treatment-naive subjects with HIV/HCV genotype 1 coinfection was equivalent to that in patients with HCV monoinfection. (Rodriguez-Torres, 2013) An exploratory FDA analysis estimated the SVR rate of this regimen to be 78% among a treatment-experienced population with HCV monoinfection, including 71% in those with multiple poor pretreatment response predictors. (US FDA, 2013b) These data, along with the absence of antiretroviral drug limitations, support inclusion of this regimen as a recommended option for treatment-experienced patients with HIV/HCV coinfection.
Sofosbuvir plus RBV has not been studied in prior HCV treatment-experienced patients with HIV/HCV genotype 1 coinfection. This regimen yielded an SVR12 rate of 76% among treatment-naive HIV/HCV genotype 1-coinfected patients. (Sulkowski, 2013b) However, responses to this regimen are expected to be lower in treatment-experienced coinfected subjects based on limited data in treatment-experienced HCV-monoinfected patients treated for 12 weeks with sofosbuvir (400 mg once daily) plus weight-based RBV (1000 mg to 1200 mg daily in divided doses). (Gane, 2013a) Further, response rates are expected to be lower than those associated with the recommended and alternative regimens. This regimen should be reserved for coinfected patients who cannot tolerate IFN and do not have antiretroviral regimen options compatible with simeprevir. These patients require expert consultation with careful consideration of fibrosis stage; in some cases, deferral of therapy may be a more appropriate action.
Sofosbuvir plus PEG/RBV has not been studied in patients with HIV/HCV genotype 2 or 3 coinfection in whom previous IFN-based HCV therapy has failed. However, recognizing the potential limitations of sofosbuvir plus RBV in more difficult to treat genotype 2 and 3 patients, particularly those with prior nonresponse and cirrhosis, the addition of IFN to the regimen can be considered for those patients who are eligible. The LONESTAR-2 (open-label, single-site, single-arm phase 2 trial) evaluated PEG (180 & #956;g weekly), sofosbuvir (400 mg once daily), and weight-based RBV (1000 mg to 1200 mg daily in divided doses) for 12 weeks in HCV-monoinfected treatment-experienced patients with genotype 2 or 3 infection. Cirrhosis was present at baseline in 55% of patients. Overall, SVR12 was achieved in 96% (22 of 23) of those with genotype 2 infection. SVR occurred in 93% (13/14) and 100% (9 of 9) of patients with and without cirrhosis, respectively. Because sofosbuvir is safe and effective when used to treat HIV/HCV-coinfected patients, the combination of sofosbuvir plus PEG/RBV for 12 weeks can be considered for appropriate genotype 2 and 3 HIV/HCV-coinfected patients.
Due to its prolonged treatment course, adverse effects, and poor response rates, PEG/RBV is no longer recommended for the treatment of patients with HCV genotypes 1, 2, 3, or 4 who are coinfected with HIV. Neither telaprevir nor boceprevir is approved for use in patients with HIV/HCV coinfection. However, when combined with PEG/RBV and used for 48 weeks, these drugs have reported efficacy and safety in patients with HIV/HCV genotype 1 coinfection similar to that in patients with HCV genotype 1 monoinfection. (Sulkowski, 2013d); (Sulkowski, 2013a) Ongoing Phase III trials will investigate the use of RGT for select patient groups. Telaprevir and boceprevir are each substrates and inhibitors of CYP3A4 and thus have substantial drug interactions with antiretroviral drugs. (van Heeswijk, 2011a); (van Heeswijk, 2011b); (Kakuda, 2012); (Johnson, 2013); (Kasserra, 2011); (Hulskotte, 2013); (Garraffo, 2013); (de Kanter, 2012); (Hammond, 2013); (Vourvahis, 2013) Due to the adverse effect profile, prolonged required course of PEG/RBV, and substantial drug interactions, these agents are no longer recommended for HIV/HCV-coinfected patients.
Because of their limited activity in vitro and in vivo against HCV genotypes 2 and 3, boceprevir, telaprevir, and simeprevir should not be used as therapy for HIV/HCV-coinfected patients with HCV genotype 2 or 3 infection. Boceprevir and telaprevir also have limited activity against HCV genotype 4 and should not be used as therapy for HIV/HCV coinfected patients with HCV genotype 4 infection. There are currently not enough data to support a recommendation for the use of simeprevir for genotype 4 infection in HIV/HCV-coinfected patients.
2. Patients with Cirrhosis
The summary of recommendations for patients with cirrhosis is in the box.
This statement is supported by a number of studies (described above) that included patients with compensated cirrhosis who were evaluated in sub-group analyses.
In one study, 61 patients with HCV infection and hepatocellular carcinoma meeting MILAN criteria for liver transplant were treated with sofosbuvir plus RBV for up to 48 weeks. (Curry MP, 2013) At the time of treatment initiation, the median MELD score was 8 (range: 6-14), and 17 patients had CTP scores of 7 or 8 (CTP Class B). To date, 44 patients have undergone liver transplantation, of whom 41 (93%) had HCV RNA below the lower limit of quantification. At 12 weeks post-transplant, 23 of 37 (62%) had no detected HCV RNA consistent with prevention of recurrent HCV infection. In the post-transplant period, 10 patients experienced recurrent HCV infection. Among the 10 patients who experienced recurrent graft infection, 9 had HCV RNA not detected for less than 30 days pretransplant. The most common adverse effects were fatigue, anemia, and headache; adverse effects led to treatment discontinuation for 2 patients (3%).
In a sofosbuvir compassionate-use program for patients with severe recurrent HCV infection following liver transplantation who were predicted to have a less than 6-month survival, (Forns, 2013b) 44 patients were treated with sofosbuvir plus RBV 32 patients were also given PEG. At treatment initiation, the median MELD score was 16 (range: 6-43), and fibrosing cholestatic hepatitis was documented in 20 patients. After week 12 of treatment, 91% of patients treated with sofosbuvir plus RBV and 75% of those treated with the addition of PEG achieved HCV RNA less than the lower limit of quantification. Of 27 patients evaluated at 12 weeks post-treatment, 15 patients (56%) achieved SVR. Overall, 75% had improved or stable clinical liver disease including improvement in hyperbilirubinemia and coagulopathy as well as decrease in MELD score. In this very sick population, 8 patients died, most from liver disease progression.
IFN should not be given to patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C) because of the potential for worsening hepatic decompensation. Neither telaprevir nor boceprevir should be used for this population because they must be coadministered with PEG/RBV. Very minimal data exist for the use of simeprevir in patients with decompensated cirrhosis. Until additional data become available, simeprevir should not be used in patients with decompensated cirrhosis.
3. Patients Who Develop Recurrent HCV Infection Post-Liver Transplantation
The summary of recommendations for patients who develop recurrent HCV infection post-liver transplantation is in the box.
Simeprevir has not been studied with sofosbuvir in the posttransplant setting. The coadministration of single-dose cyclosporine with simeprevir resulted in a 19% increase in cyclosporine concentrations and no change in simeprevir concentrations (see simeprevir package insert). However, in an interim analysis of an ongoing study (TMC435HPC3016), concomitant use of simeprevir (plus daclastavir and RBV) with cyclosporine at steady state resulted in an approximately 6-fold increase in plasma concentrations of simeprevir compared with historical data of simeprevir in the absence of cyclosporine (personal communication). This interaction may be due to inhibition of OATP1B1, P-gp and CYP3A by cyclosporine. Although the current FDA labeling does not recommend against the coadministration of simeprevir and cyclosporine, given these new findings, simeprevir should not be coadministered with cyclosporine.
The coadministration of single-dose tacrolimus with simeprevir did not result in a significant change of tacrolimus concentrations (see simeprevir package insert). In an ongoing study, concomitant use of simeprevir with tacrolimus also resulted in a 2-fold increase in plasma concentrations of simeprevir compared with historical data (personal communication). Based on phase I studies, a 2-fold increase in simeprevir concentrations is unlikely to be clinically significant.
Clinicians may consider the use of sofosbuvir plus simeprevir in patients receiving tacrolimus with therapeutic drug monitoring, particularly in those expected to have difficulty tolerating RBV (eg, patients with impaired renal function and anemia). Consideration should be given to pretreatment resistance testing for the Q80K polymorphism in genotype 1a-infected patients.
In addition to the sofosbuvir compassionate-use program, (Forns, 2013a) 40 patients with recurrent HCV infection following liver transplantation were treated for 24 weeks with sofosbuvir (400 mg daily) plus RBV (starting at 600 mg daily followed by dose escalation as tolerated). (Charlton, 2013) At study entry, patients were required to be at least 6 months post-transplant, to have a CTP score of 7 or lower, and to have a MELD score of 17 or lower. Bridging fibrosis or cirrhosis was documented in 25 patients (63%). At the end of treatment, all patients had HCV RNA levels below the lower limit of quantification and, at 4 weeks after treatment discontinuation, 27 of 35 patients (77%) had undetectable levels of HCV RNA. The most common adverse events were fatigue, headache, and arthralgia. Anemia was reported in 20% of patients. Two patients discontinued therapy due to adverse events. No deaths, graft loss, or episodes of rejection were reported.
The addition of PEG to sofosbuvir plus RBV may also be considered in the absence of contraindications.
Telaprevir or boceprevir should not be used in the post-liver transplant population because of surrounding toxicity and drug interactions with calcineurin inhibitors.
4. Patients with Renal Impairment, Including Severe Renal Impairment (CrCl <30 mL/min) or ESRD Requiring Hemodialysis or Peritoneal Dialysis
Summary of Recommendations for Patients with Renal Impairment Including, Severe Renal Impairment (CrCl <30 mL/min) or ESRD Requiring Hemodialysis or Peritoneal Dialysis is found in the Unique Patient Populations: Renal Impairment Box.
Sofosbuvir enters the hepatocyte, where it is metabolized to its active form, GS-461203. The downstream inactive nucleoside metabolite GS-331007 is almost exclusively eliminated from the body renally, mediated through a combination of glomerular filtration and active tubular secretion. Results of phase 2 and 3 sofosbuvir clinical trials have excluded patients with serum Cr level above 2.5 and/or CrCl level below <60 mL/min. The pharmacokinetics of a single dose of sofosbuvir 400 mg was assessed in persons not infected with HCV (study P7977-0915) with mild (estimated glomerular filtration rate [eGFR] >50 and <80 mL/min/1.73m2), moderate (eGFR >30 and <50 mL/min/1.73m2), severe renal impairment (eGFR <30 mL/min/1.73m2) and persons with ESRD requiring hemodialysis. Relative to persons with normal renal function (eGFR>80 mL/min/1.73m2), the sofosbuvir AUC(0-inf) was 61%, 107%, and 171% higher in subjects with mild, moderate, and severe renal impairment, respectively. The GS-331007 AUC(0-inf) was 55%, 88%, and 451% higher, respectively. No safety signals have been seen under similar conditions. In subjects with ESRD (relative to subjects with normal renal function), sofosbuvir and GS-331007 AUC (0-inf) was 28% and 1280% higher, respectively, when sofosbuvir was dosed 1 hour before hemodialysis, compared with 60% and 2070% higher, respectively, when sofosbuvir was dosed 1 hour after hemodialysis. No dose adjustment is required for patients with mild or moderate renal impairment. The safety of sofosbuvir has not been established in patients with severe renal impairment or ESRD. Therefore, a dose recommendation cannot be provided for these populations at this time, although a dedicated study to evaluate optimal dosing of sofosbuvir in HCV-infected patients with severe renal impairment or ESRD on hemodialysis is currently underway.
Simeprevir is primarily metabolized by liver CYP3A4, and renal clearance plays an insignificant role (<1%) in the elimination of simeprevir and its metabolites.
Simeprevir 150 mg daily for 7 days has been studied in non-HCV infected patients with severe renal impairment (eGFR<30 mL/min/1.73m2) and healthy volunteers (eGFR> mL/min/1.73 m2). For persons with severe renal impairment, simeprevir Cmin, Cmax, and AUC(24 hour) were 71%, 34%, and 62% higher, respectively, compared with matched healthy controls. Simeprevir exposure was higher in patients with severe renal impairment (steady-state by day 7), but no significant difference was observed in simeprevir plasma protein binding. Simeprevir was generally safe and well tolerated in subjects with severe renal impairment. Therefore, no dose adjustment of simeprevir is required in these patients. No clinically significant differences in pharmacokinetics were observed in HCV-uninfected participants with mild, moderate, or severe renal impairment. CrCl level was not identified as a significant covariate of simeprevir population pharmacokinetics in HCV-infected patients.Simeprevir has not been evaluated in patients receiving hemodialysis.
HCV infection is a major health problem in patients with ESRD. The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk for nosocomial transmission. The kidney is important for the catabolism and filtration of both IFN and RBV, and therefore, reduced doses of both PEG and RBV are warranted in patients with ESRD.
Impaired excretion of RBV occurs in patients with chronic kidney disease, as RBV is mostly eliminated by the kidney. Very little RBV is removed via dialysis. Thus, the drug can accumulate, exacerbating hemolysis in the dialysis population already at substantial risk for anemia. If a decision is made to use RBV in patients on maintenance hemodialysis, it should be used only after the implementation of several safety precautions, including (1) administering very low doses of RBV (200 mg daily), (2) monitoring hemoglobin levels on a weekly basis, (3) titrating epoetin alfa to treat anemia, and (4) providing intravenous iron supplementation to boost erythropoietin activity.
Dose adjustments needed for patients with renal impairment are summarized in the Renal Impairment Table.